2-(2-imino-alkyl or 2-imino-cycloalkyl)-phenols from o-phenyl ketoximes



United States Patent 3,547,997 Z-(Z-IMINO-ALKYL OR Z-IMINO-QYCLUALKYIJ-PHENOLS FROM U-PHENYL KETOXIMES Aram Mooradian, Schodack, and Paul E.Dupont, Me-

nands, N.Y., assignors to Sterling Drug Inc., New York, N.Y., acorporation of Delaware No Drawing. Filed May 9, 1967, Ser. No. 637,093Int. Cl. C07c 119/00 U.S. Cl. 260-566 14 Claims ABSTRACT OF THEDISCLOSURE 2-(2-iminoalkyl)-phenols are prepared by a novelrearrangement process of reacting in the approxiate range of 20 to 40 C.an O-phenyl ketoxime with a strong acid in a non-aqueous medium. Thenovel 2-(2-imino-alkyl)- phenols have antibacterial properties and arereadily hydrolyzed to the corresponding Z-(Z-keto-alkyl)-p henols whichare useful as intermediates for the preparation of benzofuranderivatives.

This invention relates to a novel rearrangement process for preparing2-(2-imino-alkyl)-phenols and to said phenols.

The invention sought to be patented, in its process aspect, resides inthe process for producing a 2-(2-iminoalkyl)-phenol which comprisesreacting in the approximate range of 20 to 40 C. an O-phenyl ketoximewith a strong acid in a nonaqueous medium. Preferred ketoximes becauseof their ready availability are O-phenyl ketoximes of low molecularweight ketones, e.g., a di- (lower-alkyDketone, a cycloalkanone havingfive to six ring carbon atoms, a lower-alkyl phenyl ketone.

The invention sought to be patented, in its composition aspect, residesin the class of compounds which are produced by the above process andwhich we designate 2-(2- imino-alkyl)-phenols. Accordingly, we depictthese compounds as having 2-imino-alkyl attached to the 2- orortho-position of a phenol. The tangible embodiments of this compositionaspect of the invention are isolated in the form of their acid-additionsalts, preferably hydrochlorides, and are readily converted byhydrolysis to the corresponding 2-(2-keto-alkyl)-phenols which areuseful intermediates for the preparation of benzofuran derivatives whichhave chemotherapeutic, e.g., antibacterial, and pharmacological, e.g.,anti-inflammatory, properties, as determined by standard evaluationprocedures.

Another composition aspect of the invention sought to be patentedresides in the compound, 2- (2-hydroxy-5- nitrophenyl)cyclopentanone,which was found to possess the inherent applied use characteristics ofhaving chemotherapeutic, e.g., antibacterial, properties, as determinedby standard chemotherapeutic evaluation procedures.

The term lower-alkyl," as used throughout this specification, means analkyl radical having from one to six carbon atoms inclusive, illustratedby methyl, ethyl, isopropyl, npropyl, n-butyl, sec-butyl, isobutyl,n-amyl, n-hexyl, and the like.

The term lower-alkanoy, as used throughout this specification, meansalkanoyl radicals having from one to six carbon atoms inclusive whichcan be arranged as straight or branched chains, among which are, forpurposes of illustration but without limiting the generality of theforegoing, formyl, acetyl, propionyl (n-propanoyl), isobutyryl(Z-methyl-n-propanoyl) and caproyl (nhexanoyl).

The manner and process of making and using the instant invention willnow be generally described so as to enable a person skilled in the artof chemistry to make and use the same, as follows:

Preparation of intermediate O-phenyl ketoximes.- These intermediates,some of which are known and some of which are novel, are prepared byvarious known procedures. For example, some are prepared by reacting ametal salt of the ketoxime in a polar solvent, e.g., dimethyl sulfoxide,tetrahydrofuran, acetonitrile, dimethylforniamide or dimethylacetamide,with an ortho-substitutable active phenyl halide, i.e., :a phenyl halidewhere phenyl is unsubstituted at one ortho position and is substitutedat either one or both of the para and the other ortho positions by a lowmolecular weight electron withdrawing group, as illustrated hereinbelow.The reaction is usually exothermic and is carried out by mixing thereactants in the solvent and agitating the reaction mixture until thereaction is complete. Gentle heating, up to about 50 to C., might benecessary to start the reaction in some instances wherein gentle heatingis then continued to ensure completion of the reaction. Alkali metalsalts of the oximes are preferred because of their ready availabilityand ease of preparation by generally known procedures, e.g., by reactingsodium hydride or potassium alkoxide with the oxime. The foregoingparticular intermediates, their preparation and their conversion tobenzofurans by heating in an acidic medium are disclosed and, in part,together with some of the resulting benzofurans are claimed in theMooradian copending U.S. patent application Ser. No. 596,395, filed Nov.23, 1966.

Other O-phenyl ketoximes can be prepared by other means. For example,ketoximes where O-phenyl is unsubstituted or substituted by groups otherthan electron withdrawing groups illustrated above are prepared byheating, preferably by refluxing in a suitable solvent, e.g., ethanol,an O-phenylhydroxylamine and a ketone in the presence of a trace of astrong inorganic acid, e.g., hydrogen chloride.

Conversion of O-phenyl ketoximes to 2 (Z-iminoalkyl)-phenols.-This novelrearrangement conversion is carried out by reacting in the approximaterange of 20 to 40 C. an O-phenyl ketomixe with a strong acid in anonaqueous medium to form a 2-(2-imino-alkyl)-phenol. The reaction isreadily conducted by contacting the reactants in a nonaqueous mediumwithin said approximate temperature range. Temperatures above this rangeshould ordinarily be avoided since the yield of the product .isundesirably diminished because of formation of by-products. Attemperatures below said range the rate of reaction is ordinarily tooslow for practical purposes and .the reaction time is undesirablyprolonged. The time necessary for conversion of the O-phenyl ketoxime to2- (2-imino-alkyl)phenol varies from about four hours to about eighteenhours or longer, depending upon the temperature used and relativereactivity of the reactants. Progress of the reaction can be followedusing thin layer chromatography to ascertain relative quantities of thestarting O-phenyl ketoximes and 2 (2-imino-a1kyl)- phenol product. Thereaction is usually mildly exothermic and is conveniently run byreacting, preferably at about 25 to 35 C., the O-phenol ketoxime with ahydrogen halide, preferably hydrogen chloride, in a lorwer-alkanoicacid, preferbaly acetic acid, or a lower-alkanol preferably ethanol.Moderate warming up to approximately 40 C., can be used to effectdissolution of the ketoxime. Modifications of the foregoing process willbe apparent to a chemist skilled in the art: for example, other stronginorganic acids, e.g., hydrogen bromide, hydrogen iodide, hydrogenfluoride, sulfuric acid, boron trifluoride etherate, and the like, orstrong organic sulfonic acids, e.g., methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, andthe like, can be used; and, further, other suitable nonaqueous solvents,

e.g., tetrahydrofuran, dioxane, ether, and the like, can be used toprovide the nonaqueous reaction medium.

For purpose of illustration but without limiting the generality of theforegoing, the conversion is ilustrated for preferred embodiments asfollows:

where Q and Q are each hydrogen, lower-alkyl, halo, lower-alkoxy, nitro,trihalomethyl, carbo-(lower-alkoxy), carboxy, cyano, lower-alkanoyl,phenylsulfonyl, N,N-di- (lower-alkyl)sulfamyl, and the like; R islower-alkyl or phenyl; R is hydrogen, alkyl having from one to fivecarbon atoms; or, R and R are attached to form in II, Z-iminocyclopentylor 2-iminocyclohexyl. Variations of the above preferred structures ofFormulas I and II encompassed in the process of the invention will beapparent to the chemist.

The molecular structure of the 2-(2-imino-alkyl)- phenols andcorresponding 2-(2-keto-alkyl)-phenols were assigned on the basis ofstudy of their infrared and NMR spectra, and confirmed by thecorrespondence of calculated and found values for the elementaryanalyses for representative examples.

The best mode contemplated for carrying out the invention will now beset forth as follows:

(A) PREPARATION OF INTERMEDIATE O-PHENYL KETOXIMES (1)O-(4-nitrophenyl)acetone oxime.-The solution of 3.65 g. of acetone oximein 125 ml. of dimethyl sulfoxide 5 was added 2.15 g. of a 56% dispersionof sodium hydride in mineral oil. The resulting mixture was stirred forfifteen minutes and then there was added 10.1 g. of 4-bromonitrobenzene. After the subsequent exothermic reaction and bubblinghad subsided, the reaction mixture was poured into water and theresulting brown precipitate was collected. The solid was suspended inalcohol and water added to the suspension. The solid that separated wascollected, dried and recrystallized from isopropyl alcohol to yield 4.9g. of O-(4-nitrophenyl)acetone oxime, M.P. 104-106 C.

(2) O-(2,4-dinitrophenyl)acetone oxime M.P. 87- 91 C., was preparedfollowing the procedure of Example A(l) by reacting the sodium salt ofacetone oxime and 2,4 dinitrochlorobenzene in tetrahydrofuran for twohours.

(3) (4 nitrophenyl)acetophenone oxime, M.P. 122124 C., was prepared asin Example A(l) by refiux'ing the sodium salt of acetophenone oxime and4- nitrofiuorobenzene in tetrahydrofuran for ten hours.

(4) O-(2 nitrophenyl)acetone oxime, M.P. 5659 C., was prepared as inExample A(l) by stirring the sodium salt of auetone oxime and2-nitrobromobenzene in dimethyl sulfoxide for forty-five minutes.

, (5) O-(2 carboxy-4-nitrophenyl)acetone oxime-To a solution of 20.1 g.of 2-chloro-5-nitrobenzoic acid in 250 ml. of tetrahydrofuran was addedwith stirring 4.27 g. of a 56.2% dispersion of sodium hydride in mineraloil."Sufficient dimethyl sulfoxide was added to the suspension to effectdissolution. A solution of 7.3 g. of acetone oxime in 100* ml. oftetrahydrofuran was heated with 4.27 g. of 56.2% sodium hydride followedby addition of 50 ml. of dimethyl sulfoxide. The mixture was heated withstirring until evolution of hydrogen had ceased (about fifteen minutes)and then poured into the solution of the benzoic acid salt. Theresulting suspension was first stirred at room temperature for aboutforty-five minutes and then heated at reflux for about ninety minutes.The reaction mixture was next treated with water and the tetrahydrofuranwas removed by distilling in vacuo.

The remaining aqueous layer was extracted with n-pentane to remove themineral oil, treated with decolorizing charcoal and filtered, and thefiltrate acidified with 10% aqueous hydrochloric acid. The solid thatseparated was collected and recrystallized from ethyl acetate to yield16.0 g. of O-(2-carboxy-4-nitrophenyl)acetone oxime, M.P. 169171 C.(with decomposition).

(6) O-(2 nitro-4-trifiuoromethylphenyl)acetone oxime, M.P. 5255 C., wasprepared as in Example A(l) by stirring at room temperature for one hourthe sodium salt of acetone oxime and 4-chloro-3-nitrobenzotrifiuoride indimethyl sulfoxide. After pouring the reaction mixture into ice andwater, the product was obtained by extracting with ether, evaporatingoff the ether, and recrystallizing from ethanol and then from n-hexane.

(7) O-(4-trifluoromethylphenyl)acetone oxime.-To 200 ml. of drydimethylformamide was added 7.3 g. of acetone oxime and 11.2 g. ofpotassium tertiary-butoxide. The resulting mixture was stirred for a fewminutes and then there was added 16.4 g. of 4-fluorobenzotrifluoride andthe reaction mixture was heated with stirring for three hours on a steambath. It was then poured into water whereupon the crystalline productseparated. The product was collected and recrystallized from n-pentane,using decolorizing charcoal, to yield 12.6 g. ofO-(4-trifluoromethylphenyl)acetone oxime, M.P. 46-49 C.

(8) O-(4-cyanophenyl)acetone oxime, M.P. 103 C., was prepared as inExample A(6) by stirring at about 50-60 C. for one hour a mixture of thepotassium salt of acetone oxime (using potassium tertiary-butoxide) and4-fluorobenzonitrile in dimethyl sulfoxide.

(9) O-(4-nitrophenyl)cyclohexanone oxime.-To a solution of 17 g. ofcyclohexanone oxime in 100 ml. of dimethyl sulfoxide and 300 ml. oftetrahydrofuran was added 6.45 g. of a 56% solution of sodium hydride inmineral oil. This mixture was stirred until most of the bubblingsubsided and then there was added 23.7 g. of 4-chloronitrobenzene. Afterthe reaction mixture had been stirred for an additional six hours atroom temperature, the tetrahydrofuran was then removed by distill ing invacuo and water was added to the residue. The crystalline product wascollected and recrystallized twice from isopropyl alcohol to yield 12.5g. of O-(4-nitrophenyl)cyclohexanone oxime, M.P. 99101 C.

10) 4- (4-nitrophenoxy)imino] cyclohexyl benzoate, M.P. 123.5125.0 C.,was prepared as in Example A(6) by reacting the potassium salt of4-benzoyloxycyclohexanone oxime and 4-fiuoronitrobenzene indimethylacetamide for about fifteen mniutes.

The above intermediate 4-benzoyloxycyclohexanone oxime was prepared asfollows: A reaction mixture containing 43.6 g. of4-benzoyloxycyclohexanone, 15.3 g. of hydroxylamine hydrochloride andml. of pyridine was heated on a steam bath for four hours and thenpoured into one liter of water. The oil that separated was extractedwith ether. The ether extract was washed with water, dried overanhydrous magnesium sulfate and calcium sulfate, treated withdecolorizing charcoal and filtered, and the ether removed by vacuumdistillation. The aqueous layer was removed by decantation and theremaining oil was washed several times with water whereupon the oilsolidified. The solid was collected, washed with water, dried in avacuum oven at 45 for two hours, and recrystallized twice from ether toyield 26 g. of crystalline 4-benzoyloxycyclohexanone oxime, M.P. 106108C.

(11) O-(4-nitrophenyl)-2butanone oxime, M.P. 41- 42 C., was prepared asin Example A(6) by stirring a mixture of the sodium salt of Z-butanoneoxime and 4- fiuoronitrobenzene in tetrahydrofuran for two hours.

(12) O-(4-trifiuoromethylphenyl)acetophenone oxime, M.P. 9497 C., wasprepared as in Example A(l) by refluxing for three hours a mixture ofthe sodium salt of acetophenone oxime and 4-fluorobenzotrifluoride in amixture of tetrahydrofuran and dimethyl sulfoxide.

(13) O-(2-chloro-4-nitrophenyl)acetone oxime, M.P. 117119 C., wasprepared as in Example A(l) by heating on a steam bath for six hours astirred mixture of the potassium salt (using potassium tert-butoxide) ofacetone oxime and 3,4-dichloronitrobenzene in dimethylformamide.

(14) O-(4 N,N dimethylsulfamylphenyl)acetophenone oxime, M.P. 95-97 C.,was obtained as in Example A(6) by stirring with no external heating fortwo hours a mixture of the sodium salt of acetophenone oxime andN,N-dimethyl 4 fiuorobenzenesulfonamide in a mixture of tetrahydrofuranand dimethyl sulfoxide. The oxime product was recrystallized from ether.

(15) O-(4 carbethoxyphenyl)acetophenone oxime, M.P. 5254 C., fromn-heptane, was prepared as in Example A(1) by heating on a steam bathwith stirring for two hours the sodium salt of acetophenone oxime andethyl 4-fiuorobenzoate in a mixture of tetrahydrofuran and dimethylsulfoxide.

(16) O-(4-acetylphenyl)acetone oxime, M.P. 5053 C., from n-hexane, wasprepared as in Example A(7) by stirring at room temperature for threehours the potassium salt of acetone oxime and 4-fluoroacetophenone indimethyl sulfoxide.

(17) O-(4-phenylsulfonylphenyl)acetone oxime, M.P. 130-134" C., fromisopropyl alcohol, was prepared as in Example A(l) by mixing withstirring the sodium salt of acetone oxime and 4-fluorophenyl phenylsulfone in a mixture of tetrahydrofuran and dimethyl sulfoxide andallowing the reaction mixture to stand at room temperature for threedays.

(18) O-(4-N,N dimethylsulfamylphenyl)-4-methoxyacetophenone oxime, M.P.135137 C., from ethanol, was prepared as in Example A(l) by heating on asteam bath for two hours a stirred mixture of the sodium salt of4-rnethoxyacetophenone oxime and N,N-dimethyl-4-fluorobenzenesulfonarnide in a mixture of tetrahydrofuran and dimethylsulfoxide.

(19) -(2 nitrophenyl)-4-methoxyacetophenone oxime, M.P. 111-113" C.,from isopropyl alcohol, was prepared as in Example A( 1) by heating on asteam bath for two hours a stirred mixture of the sodium salt of4-methoxyacetophenone oxime and 2-chloronitrobenzene in a mixture oftetrahydrofuran and dimethyl sulfoxide.

(20) O-(4-carbethoxypheny1) 4 methoxyacetophenone oxime, M.P. 9092 C.,from isopropyl alcohol, was prepared as in Example A(l) by heating on asteam bath for three hours a stirred mixture of the sodium salt of 4-methoxyacetophenone oxime and ethyl 4-fiuorobenzoate in a mixture oftetrahydrofuran and dimethyl sulfoxide.

(21) O-(4 nitrophenyl)cyclopentanone oxime, M.P. 128130 C., fromn-hexane, was prepared as in Example A(l) by heating on a steam bath fortwo hours a stirred mixture of the sodium salt of cyclopentanone oximeand 4-fluoronitrobenzene in a mixture of tetrahydrofuran and dimethylsulfoxide.

(22) O-(Z-trifluoromethylphenyl)acetophenone oxime, an oil, was preparedas in Example A( 6) by heating on a steam bath a stirred mixture of thesodium salt of acetophenone oxime and 2-fiuorobenzotrifluoride in amixture of tetrahydrofuran and dimethyl sulfoxide.

(23) O-phenylacetophenone oxime-A solution containing 5.3 g. ofO-phenylhydroxylamine and 5.9 g. of acetophenone in 100 ml. of ethanolcontaining a trace of hydrogen chloride was heated on a steam bath atreflux for three hours. The solvent was then distilled oif in vacuo toyield 9.9 g. of O-phenylacetophenone oxime. Substitution of a molarequivalent quantity of O-(4-toyl)hydroxylamine or0-(4methoxyphenyl)hydroxylamine for O- phenylhydroxylamine in the aboveprocedure yields 0-(4- tolyl)acetophenone oxime orO-(4-methoxyphenylacetophenone oxime, respectively.

(24) O-(4-chlorophenyl) acetone oxime.-A solution containing 12.8 g. ofO-(4-chlorophenyl)hydroxylamine and 5.2 g. of acetone in 50 ml. ofabsolute ethanol con- All taining about drops of concentratedhydrochloric acid was refluxed for about forty minutes and then allowedto stand overnight at room temperature. The solvent was distilled off invacuo and the residual oily material was distilled under reducedpressure to yield 6.9 g. of 0-(4- chlorophenyl)acetone oxime, B.P. 5560C. at 0.05-0.10 mm. Substitution of O-(2,4-dichlorophenyl)hydroxylamineor O-(4-bromophenylhydroxylamine for O-(4- chlorophenyl)hydroxylamine inthe above procedure yields, respectively, O-(2,4-dich1orophenyl)acetoneoxime or O-(4-bromophenyl)acetone oxime.

O (4-nitro-2-trifiuoromethylphenyl)acetone oxime, M.P. 87-90 C., wasprepared as in Example A(l) by stirring at room temperature for twohours the sodium salt of acetone oxime and4-chloro-3-trifluoromethylnitrobenzene in a mixture of tetrahydrofuranand dimethyl sulfoxide.

(B) CONVERSION OF O-PHENYL KETOXIMES TO 2-(2-IMINO-ALKYL)PHENOLS (1)2-(2-iminopropyl) 6 nitrophenoL-A solution containing 12.0 g. ofO-(2-nitrophenyl)acetone oxime and 50 ml. of 1.8 N hydrogen chloride inacetic acid (oxime dissolved by gently warming the acetic acid solutionto about 40 C.) was allowed to stand at room temperature for twenty-fourhours. The reaction mixture was treated with ether and the resultingprecipitate was collected, dried in vacuo at C. to yield 11.2 g. of theyellow crystalline 2-(2-iminopropyl)-6-nitrophenol as its hydrochloride,M.P. 151 C. with decomposition. A second crop of 1.5 g. of the productwas obtained from the filtrate. The structures of this and subsequent2-(2-iminoalkyl)-phenols produced by the process of the invention wereconfirmed by their infrared. and nuclear magnetic resonance spectralanalyses, and by their elementary analyses.

The following compounds were prepared using the above procedure ofExample B( 1) and the appropriate O-phenyl ketoxime. The compoundscrystallized out of the reaction mixture without the addition of anyether. The reaction mixture was allowed to stand at room temperature forabout sixteen hours unless otherwise noted.

(2) 2-(2-iminopropyl)-4-nitrophenol as its hydrochloride, 21.6 g. (94%yield), M.P. 171 C., using 19.4 g. of O-(4-nitrophenyl)acetone oxime inml. of 1.8 N hydrogen chloride in acetic acid.

(3) 2-[2-imino-2-(4-methoxyphenyl)ethyl] '6 nitrophenol as itshydrochloride, 8.6 g. (67%), M.P. 194 C., from methanol-ether as yellowneedles, using 11.5 g. of O-(2-nitrophenyl)-4-methoxyaceto phenone oximein 300 ml. of 1.8 N hydrogen chloride in acetic acid. 2-[2-imino- 2(4-methoxyphenyl)ethyl]-6-nitrophenol hydrochloride was found to have invitro bacteriostatic activity against Staphylococcus aureus at a testconcentration of 0.10 mg./ cc.

(4) 2-[2-imino 2 (4-methoxyphenyl)ethyl]-4-N,N- dimethylsulfamylphenolas its hydrochloride, 11.8 g. (88%), M.P. 213 C., using 12.1 g. ofO-(4-N,N-dimethylsulfamylphenyl)-4-methoxyacetophenone oxime and 175 ml.of 1.8 N hydrogen chloride in acetic acid. 2-[2- imino 2(4-methoxyphenyl)ethyl]-4-N,N-dimethylsulfamylphenol hydrochloride wasfound to have in vitro bacteriostatic activity against Staphylococcusaureus at a test concentration of 0.10 mg/ cc.

(5) 4-cyano-2-(Z-iminopropyl)-phenol as its hydrochloride, 13.0 g., M.P.205 C., using 15.0 g. of O-(4- cyanophenyl)acetone oxime and 90 ml. of1.8 N hydrogen chloride in acetic acid, and allowing the reactionmixture to stand about twenty-four hours at room tem perature.4-cyano-2-(2-iminopropyl)-pheno1 hydrochloride was found to have invitro bacteriostatic activity against Staphylococcus aureus at a testconcentration of 0.10 mg./ cc.

(6) 2-(2-imino-2-phenylethyl)-4l-nitrophenol as its hy- 7 drochloride,2.2 g., M.P. l75179 C., using 2.5 g. of O (4-nitrophenyl)acetophenoneoxime and 85 ml. of 1.8 N hydrogen chloride in acetic acid.

(7) 4-acetyl-2-(Z-iminopropyl)-phenol as its hydrochloride, 4.5 g., M.P.176 C., using 5.0 g. of O-(4-acetylphenyl)acetone oxime, 25 ml. of 1.8 Nhydrogen chloride in acetic acid and a reaction period of about fivehours at room temperature.

(8) 2-(2-imino-2-phenylethyl) 6 trifluoromethylphenol as itshydrochloride, 4.1 g., M.P. 182 C., from absolute ethanol-ether, using9.3 g. of O-(4-trifluoromethylphenyl)acetophenone oxime and 25 ml. of1.8 N hydrogen chloride in acetic acid.

(9) 2-(2-irninocyclopentyl)-4-nitrophenol as its hydrochloride, 4.9 g.,M.P. 207210 C. with decomposition, using 6.0 g. ofO-(4nitrophenyl)cyclopentanone oxime and 30 ml. of 1.8 N hydrogenchloride in acetic acid.

(10) 2-(2-imino-2-phenylethyl)phenyl as its hydrochloride, 5.8 g., M.P.210 C., from methanol-ether, using 9.9 g. of O-phenylacetophenone oximeand 50 ml. of 1.8 N hydrogen chloride in acetic acid.2-(2-imino-2-phenylethyl)-phenol hydrochloride was found to have invitro bacteriostatic activity against Staphylococcus aureus at a testconcentration of 0.05 mg./cc.

(11) 2-(2-iminocyclohexyl)-4-nitrophenol as its hydrochloride, 32.5 g.,M.P. 223 C., using 30.0 g. of O-(4- nitrophenyl)-cyclohexanone oxime and200 ml. of 1.8 N hydrogen chloride in acetic acid.

(12) 2-(2-iminopropyl)-4-phenylsulfonylphenol as its hydrochloride, 21.4g., M.P. 198 C., using 20.0 g. of O-(4-phenylsulfonylphenyl)acetoneoxime, 210 ml. of 1.8 N hydrogen chloride in acetic acid and a reactionperiod of about four hours at room temperature.

(13) 2-(2-iminopropyl)-4,6-dinitrophenol as its hydrochloride, 7.7 g.,M.P. 174l76 C. with decomposition, using 20.0 g. of O (2,4dinitrophenyl)acetone, oxime 125 ml. of 1.8 N hydrogen chloride inacetic acid and a reaction period of about two days at room temperature.

(14) 2-(2-iminopropyl)-4-trifiuoromethylphenol as its hydrochloride, 3.8g., M.P. 159 C., using 4.6 of O-(4- trifluoromethylphenyl)acetone oximeand 30 ml. of 1.8 N hydrogen chloride in acetic acid.

(15) 4-chloro-2-(2-irninopropyl)phenol as its hydrochloride, 5.5 g.,M.P. 156 C., using 6.8 g. of O-(4'chlorophenyl)acetone oxime, 50 ml. of1.8 N hydrogen chloride in acetic acid, a reaction period of abouttwenty-four hours and addition of ether to the reaction mixture toprecipitate the product.

Similarly, the other O-phenyl ketoximes of Example A are converted as inExample B(1) to the corresponding 2-(2-imino-alkyl)-phenols as theirhydrochlorides.

(16) Z-(Z-iminopropyl)-4-nitrophenol as its hydrochloride also wasprepared as in Example B(2) except the reaction mixture of 1.0 g. ofO-(4-nitrophenyl)acetone oxime and 20 ml. of 6 N ethanolic hydrogenchloride was kept at 40 C. (using an external bath of refluxingmethylene chloride) for about sixteen hours.

(17) 2-(2-iminopropyl)-4-nitrophen0l in the form of other acid-additionsalts was obtained following the procedure of Example B(2) but using 1.0g. of O-(4-nitrophenyl)acetone oxime in each instance and the indicatedquantities of other strong acids in place of hydrogen chloride, forexample: 2-(2-iminopropyl)-4-nitrophenol hydrobromide using 10 ml. ofhydrogen bromide in acetic acid; 2-(2-iminopropyl)-4-nitrophenolmethanesulfonate using 2.0 g. of methanesulfonic acid and 10 ml. ofacetic acid; 2-(2-iminopropyl)-4-nitrophenol hydrogen sulfate using 0.38ml. of concentrated sulfuric acid and 7.6 ml. of acetic acid;2-(2-iminopropyl)-4-nitrophenol boron trifluoride using 8 ml. of borontrifluoride etherate and 5 ml. of acetic acid. The reactions withmethanesulfonic acid and p-toluenesulfonic acid were carried out at roomtemperature for about sixteen hours (overnight) and the reactions withhydrogen bromide, sulfuric acid and boron trifluoride etherate, at roomtemperature for three days (over the weekend). The respective acidaddition salts were readily hydrolyzed as in Example B(1) to yield3-acetonyl-4-nitrophenol.

(C) CONVERSION OF 2- (Z-IMINO-ALKYL) -PHE- N OLS TO 2- Z-KETO-ALKYL-PHENOLS (1) 3-acetonyl-4-hydroxybenzonitrile.About ml. of water wasmixed with 10.0 g. of 4-cyano-2-(iminopropyl)-phenol hydrochloridewhereupon the salt dissolved and soon thereafter there separated theproduct, which was collected, washed with water, dried overnight invacuo at 60 C. to yield 7.4 g. (89% yield) of 3-acetonyl-4hydroxybenzonitrile, M.P. 149 C.

(2) 2-(2 hydroxy-S-nitrophenyl)cyclopentanone.A 10.3 g. portion of2-(2-iminocyclopentyl)-4-nitrophenol hydrochloride was dissolved in 200ml. of water and the solution was allowed to stand for about thirtyminutes after which time the product had separated. The product wasextracted with ethyl acetate; the extract was washed three times withwater, treated with n-pentane to cloudiness, and treated withdecolorizing charcoal; and, the mixture filtered. To the filtrate wasadded n-pentane and the solution allowed to stand whereupon thereseparated only droplets of water, which were separated by decantation.The solvent was then removed by distilling in vacuo and the residue wasrecrystallized from ethyl acetate to yield 5.9 g. of2-(2-hydroxy-5-nitrophenyl)cyclopentanone, M.P. 177179 C. This compoundwas found to have in vitro bacteriostatic activity againstStaphylococcus aureus at a test concentration of 0.10 mg./cc.

(3) 1 (2-hydroxy-S-phenylsulfonylphenyl)-2-propanone.A 7.0 g. portion of2-(2-iminopropyl)-4-phenylsulfonylphenol hydrochloride was stirred with300 ml. of water, the mixture warmed on a steam bath for about tenminutes and then allowed to stand for about four hours at roomtemperature. The separated product was collected, washed successivelywith water and n-pentane, and then dried overnight in vacuo at 60 C. toyield 6.0 g. (96%) of 1-(2-hydroxy-5-phenylsulfonylphenyl)-2-propanone,M.P. -172 C.

(4) 4-hydroxy-3- 4-methoxyphenacyl) -N,N-dirnethylbenzenesulfonamide,M.P. 149.5-151.5 C., was prepared following the procedure described inExample C(3) using 6.5 g. of 2-[2-imino-2-(4-methoxyphenol)ethyl]-4-N,N-dimethylsulfamylphenol hydrochloride and 250 ml. of Water. There wasthus obtained 4.5 g. (76.3%) of the product after two recrystallizationsfrom methylene dichloride-n-hexane.

(5) 1 (2-hydroxy-5-nitrophenyl)-2-propanone, M.P. 190193 C., wasprepared following the procedure described in Example C(1) using 1.0 g.of 2-(2-iminopropyl)-4-nitrophenol hydrochloride and about 50 ml. ofwater. There was thus obtained 0.6 g. (71%) of the product after onerecrystallization from isopropyl alcohol.

(6) 4-nitro-2-phenacylphenol, M.P. l79 C., was prepared as in ExampleC(1) using 1.2 g. of 2-(2-imino- 2-phenylethyl)-4-nitrophenolhydrochloride and 50 ml. of water.

(7) 1-(5-acetyl-2-hydroxyphenyl)-2 propanone, M.P. l12-114 C., wasobtained as in Example C(1) using 2.8 g. of 4 acetyl 2(2-iminopropyl)-phenol hydrochloride and 60 ml. of water. There was thusobtained 1 g. of the product after one recrystallization from methylenedichloride-n-hexane.

(8) 2 (2 hydroxy 5 nitrophenyl)cyclohexanone, M.P. 186l90 C., wasprepared as in Example C(1) by stirring for one hour 10.0 g. of 2 (2irninocyclohexyl)- 4 nitrophenol hydrochloride in 150 ml. of water.There was thus obtained 7.1 g. of the product after onerecrystallization from acetone-n-hexane.

Similarly, the other 2 (2-imino-alkyl)-phenol acidaddition salts ofExample B are hydrolyzed as in Example C(1) to yield the corresponding 2(2 keto alkyl)- phenols.

9 (D) CONVERSION OF 2-(2-IMINO-ALKYL)- PHENOLS TO BENZOFURANS Theforegoing 2 (2 imino-alkyD-phenols as their hydrochlorides are readliyconverted to corresponding benzofuran derivatives by heating them inethanolic hydrogen chloride, as illustrated by the following conversionof 4 cyano 2 (2 imniopropyl)-phenol hydrochloride to 5 cyano 2methylbenzofuran: Gaseous hydrogen chloride was bubbled through amixture of 6.34 g. of 4- cyano 2 (2 iminopropyl) phenol hydrochloride in100 ml. of 1.8 N hydrogen chloride in acetic acid heated on a steam bathfor about thirteen hours. The reaction mixture was allowed to cool andthe solid that separated was collected and washed successively withacetic acid and ether. The filtrate was evaporated in vacuo underreduced pressure to yield more solid. The solids were combined, treatedwith aqueous sodium hydroxide solution, and the mixture extracted withether. The ether extract was washed with water, dried over anhydroussodium sulfate and evaporated in vacuo to yield a solid. The solid wasrecrystallized from ether n-hexane to yield 3.6 g. of 5-cyano-2-methylbenzofuran, M.P. 75-77 C.

Similarly, the other 2-(2-imino-alkyl)-phenol hydrochlorides of ExampleB above are converted into the corresponding benzofurans following theabove procedure for the conversion of 4-cyano-2-(2-iminopropyl)-phenolhydrochloride to 5 cyano 2 methylbenzofuran, e.g., 2 (2 iminopropyl) 6nitrophenol hydrochloride to 2 methyl 7 nitrobenzofuran, 2 [2imino-2-(4- methoxyphenyDethyl] 6 nitrophenol hydrochloride to 2 (4methoxyphenyl) 7 nitrobenzofuran, 2 (2- imino 2 phenylethyl) 4nitrophenol hydrochloride to 5 nitro 2 phenylbenzofuran, 2 (2iminocyclohexyl) 4 nitrophenol hydrochloride to 1,2,3,4 tetrahydro 8nitrodibenzofuran.

(E) CONVERSION OF 2 (2 KETO-ALKYL)- PHENOLS TO BENZOFURANS The foregoing2 (2 keto-alkyl) phenols of Example C are readily converted tobenzofurans by treatment with an acidic agent or dehydrating agent byknown procedures, e.g., l (2 hydroxy 5 nitrophenyl) 2 propanone to 2methyl 5 nitrobenzofuran or 1 (3,5-dinitro- 2 hydroxyphenyl) 2 propanoneto 5.7 dinitro 2 methylbenzofuran by heating the propanone with zincchloride in acetic acid solution; 4 nitro 2 phenacylphenol to 5 nitro 2phenylbenzofuran by heating a benzene solution of the phenacylphenol inthe presence of phosphorus pentoxide; l (2 hydroxyphenyl) 2- propanoneto 2 methylbenzofuran while standing for forty-eight hours in adesiccator over concentrated sulfuric acid; 2 phenacylphenol to 2phenylbenzofuran by heating the phenacylphenol in acetic acid solutioncontaining a little concentrated hydrochloric acid.

Similarly, the other 2 (2 keto-alkyl) phenols of Example C are convertedto benzofurans by the above known procedures, e.g., 3 acetonyl 4hydroxybenzonitrile to 5 cyano 2 methylbenzofuran, 1 (5 acetyl- 2hydroxyphenyl) 2 propanone to 5 acetyl 2- methylbenzofuran, 2 (2 hydroxy5 nitrophenyl) cyclohexanone to 1,2,3,4 tetrahydro 8 nitrodibenzofuran.

The subject matter which the applicants regard as their invention isparticularly pointed out and distinctly claimed as follows:

1. The process which comprises reacting in the approximate range of 20to 40 C. with a strong acid selected from the group consisting ofhydrogen halide, sulfuric acid, boron trifluoride etherate or strongorganic sulfonic acid in a nonaqueous medium an O-phenyl ketoxime of theformula I R1 Q1 to produce an acid-addition salt of a phenol of theformula where Q and Q are each hydrogen, lower-alkyl, halo,lower-alkoxy, nitro, trihalomethyl, carbo-(lower-alkoxy), carboxy,cyano, lower-alkanoyl, phenylsulfonyl or N,N- di-(lower-alkyl)sulfamyl,R is lower-alkyl or phenyl, R is hydrogen, alkyl having from one to fivecarbon atoms, or R and R together constitute CH CH CH or CH CH CH CH 2.The process according to claim 1 where the strong acid is a hydrogenhalide and the non-aqueous medium is a lower-alkanoic acid or alower-alkanol.

3. The process according to claim 1 where the strong acid is hydrogenchloride and the non-aqueous medium is acetic acid or ethanol.

4. The process according to claim 1 where the reaction is carried out atabout 25 to 35 C.

5. The process according to claim 1 Where the ketoxime is an O-phenyldi-(lower-alkyDketone oxime, an O-phenyl cycloalkanone oxime having fiveto six ring-carbon atoms or an O-phenyl lower-alkyl phenyl ketone oxime.

6. The process according to claim 1 where an O- phenyl-acetone oxime isreacted with a strong acid in acetic acid or ethanol to form a 2 (2iminopropyl)- phenol as its acid-addition salt.

7. The process according to claim 1 where an O-phenylacetophenone oximeis reacted with a strong acid in acetic acid or ethanol to form a 2 -(2imino 2 phenylethyl) phenol as its acid-addition salt.

8. The process according to claim 1 where an O- phenyl-cyclopentanoneoxime is reacted with a strong acid in acetic acid to form a 2 -(2iminocyclopentyl)-phenol as its acid-addition salt.

9. The process according to claim 1 where an O- phenyl cyclohexanoneoxime is reacted with a strong acid in acetic acid to form a 2 (2iminocyclohexyl)- phenol as its acid-addition salt.

10. An acid-addition salt of the imine of the formula where Q and Q areeach hydrogen, lower-alkyl, halo, lower-alkoxy, nitro, trihalomethyl,carbo-(lower-alkoxy), carboxy, cyano, lower-alkanoyl, phenylsulfonyl orN,N- di-(loWer-alkyl)sulfamyl, R is alkyl having from one to six carbonatoms or phenyl, R is hydrogen, alkyl having from one to five carbonatoms, or R and R together constitute CH CH CH or CH CH CH CH 12 and theacid-addition salt is derived from a strong acid References Citedselected from hydrogen halide, sulfuric acid, boron tri- Sheradsky TJTetrahedron Letters 43 pp 5225 fluoride etherate or strong organicsulfonic acid. 5227 11. 2 (2 iminopropyl) phenol acid-addition saltaccording to claim 1 5 LEON ZITVER, Primary Examiner 12. 2 (2 imino 2phenylethyl) henol acidaddition salt according to claim 10. P SCHWARTZAsslstant Exammer 13. 2 (2 iminocyclopentyl) phenol acid-addition Us ClXR salt according to claim 10.

14. 2 (2 iminocyclohexyl) phenol acid-addition 10 470, 556, saltaccording to claim 10.

T3 53?" UNITED STATES PATEN OFFICE CERTIFIICAflE OF CORRLCC'IIUN PatentNo. 3, 5 ,7, 997 I Dated December 15, 1970 Aram Mooradian 80 Paul E.Dupont Inventor(s) It is certified that error appears in theabove-identified patent; and that said Letters Patent are herebycorrected as shown below:

Column 1, line 14, "aporoxiate" should read --approxima' Column 2, line39, "ketomixe should read -ketoxime-; line 5 "ketoximes" should read-ketoxime-. Column 3, line 4, "ilustrated" should read --illustrated--;in the formula to t! right at about line 6, "NH.NC1" should read--NH.HCl--; betwee the formulas and line 13, insert "I" and "II",identifyin the respective formulas; line 3%, before "solution" omit "Theam place thereof insert "To a---; line 47, "oxime" should read -oxime,line 8, "auetone should read --acetone--. Colux line 68, l-(toyl shouldread --(4-toly1)--; line 71, l-methoxyphenylaceto-" should readl-methoxyphenynacetc Column 6, line '8 t-bromophenylhydroxylamine"should read -(4-bromophen l )hydroxylamine-. Column 7, line 18, ")phenyIshould read xphenol line 36, 'acetone, oxime" should reac --acetoneoxime, line 40, "4.6" should read 4.6 g.--; line 67, between"nitrophenol" and "hydrogen" insert -ptoluenesulfonate using 1.7 g. ofp-toluenesulfonic acid and l( of acetic acid; 2- (2-iminopropyl l-nitrophenol--. Column 8, line 2, "13(1) should read --c 1 Column 9 line5, "read: should read -readily--; line "-imniopropyl should readiminopropyl) line 50, "5.7" should read -5,7--. Column 10, Claim 10, inthe formula I! NH J I i should read Signed and sealed this 29th day ofJune 1971 USEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, J Attesting OfficerCommissioner of Patent

